tbuckley/cabot-search huggingface dataset:
Depletion of butyrate-producing microbes of the Firmicutes predicts nonresponse to FMT therapy in patients with recurrent <i>Clostridium difficile</i> infection
Authors: Hongliang Tian, Jiaqu Cui, Chen Ye, Jiangman Zhao, Bo Yang, Yue Xu, Shushen Ji, Le Wang, Xiaoqiong Lv, Chunlian Ma, Shailan Zhou, Ning Li, Xinjun Wang, Huanlong Qin, Qiyi Chen
Journal: Gut Microbes (2023)

Approximately 10% of individuals diagnosed with Clostridium difficile infection (CDI) show the resistance to fecal microbiota transplantation (FMT), with the underlying mechanisms remaining elusive. Deciphering the intricate microbiome profile within this particular subset of FMT-refractory patients via clinical FMT investigations assumes paramount importance, as it holds the key to designing targeted therapeutic interventions tailored for CDI, particularly recurrent CDI (rCDI). A cohort of twenty-three patients afflicted with rCDI, exhibiting congruent clinical baselines, was meticulously selected for FMT. Rigorous screening of thousands of healthy individuals identified ten FMT donors who met stringent health standards, while a total of 171 stool samples were collected to serve as healthy controls. To assess the influence of microbiome dynamics on FMT efficacy, fecal samples were collected from four donors over a continuous period of twenty-five weeks. After FMT treatment, seven individuals exhibited an inadequate response to FMT. These non-remission patients displayed a significant reduction in α-diversity indexes. Meanwhile, prior to FMT, the abundance of key butyrate-producing Firmicutes bacteria, including Christensenellaceae_R_7_group, Ruminococcaceae_unclassified, Coprococcus_2, Fusicatenibacter, Oscillospira, and Roseburia, were depleted in non-remission patients. Moreover, Burkholderiales_unclassified, Coprococcus_2, and Oscillospira failed to colonize non-remission patients both pre- and post-treatment. Conversely, patients with a favorable FMT response exhibited a higher relative abundance of Veillonella prior to treatment, whereas its depletion was commonly observed in non-remission individuals. Genera interactions in lower effectiveness FMT donors were more similar to those in non-remission patients, and Burkholderiales_unclassified, Coprococcus_2, and Oscillospira were frequently depleted in these lower effectiveness donors. Older patients were not conducive to the colonization of Veillonella, consistent with their poor prognosis after FMT. FMT non-remission rCDI patients exhibited distinct characteristics that hindered the colonization of beneficial butyrate-producing Firmicutes microbes. These findings hold promise in advancing the precision of FMT therapy for rCDI patients.
Scattered Painful Papulonodules in an Older Woman
Authors: Penelope Kim-Lim, Cristina Thomas
Journal: JAMA Oncology (2023)

A 56-year-old woman was admitted for myeloablative conditioning in preparation for allogeneic hematopoietic cell transplant. Her course was complicated by severe mucositis, acute kidney injury, and neutropenic fever. During her admission, she also developed painful necrotic skin lesions, a nonproductive cough, and altered mental status. What is your diagnosis?
Long-term Effectiveness of the National Diabetes Quality Assessment Program in South Korea
Authors: Ji Hye Huh, Serim Kwon, Gui Ok Kim, Bo Yeon Kim, Kyoung Hwa Ha, Dae Jung Kim
Journal: Diabetes Care (2023)

OBJECTIVE This study examined the long-term effectiveness of the national diabetes quality assessment program (NDQAP) in diabetes. RESEARCH DESIGN AND METHODS From the Health Insurance Review and Assessment Service database, 399,984 individuals with diabetes who visited a primary care clinic from 1 July 2012 to 30 June 2013 were included and followed up until 31 May 2021. The NDQAP included five quality assessment indicators: regular outpatient visits, continuity of prescriptions, regular testing of glycated hemoglobin and lipids, and regular fundus examination. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for diabetes complications and all-cause mortality by the achievement of quality assessment indicators. RESULTS During the mean follow-up duration of 7.6 ± 1.8 years, 20,054 cases (5.0%) of proliferative diabetic retinopathy (PDR), 6,281 end-stage kidney diseases (ESKD; 1.6%), 1,943 amputations (0.5%), 9,706 myocardial infarctions (MIs; 2.4%), 26,975 strokes (6.7%), and 35,799 all-cause mortality (8.9%) occurred. Each achievement of quality assessment indicator was associated with a decreased risk of diabetes complications and all-cause mortality. Individuals who were managed in high-quality institutions had a lower risk of PDR (HR 0.82; 95% CI 0.80–0.85), ESKD (HR 0.77; 95% CI 0.73–0.81), amputation (HR 0.75; 95% CI 0.69–0.83), MI (HR 0.85; 95% CI 0.82–0.89), stroke (HR 0.86; 95% CI 0.84–0.88), and all-cause mortality (HR 0.96; 95% CI 0.94–0.98) than those who were not managed in high-quality institutions. CONCLUSIONS In Korea, the achievement of NDQAP indicators was associated with a decreased risk of diabetes complications and all-cause mortality.
Shifting pattern of gut microbiota in pregnant women two decades apart – an observational study
Authors: Samuli Rautava, Marta Selma-Royo, Teo Oksanen, Maria Carmen Collado, Erika Isolauri
Journal: Gut Microbes (2023)

Past decades have witnessed a decrease in environmental biodiversity. We hypothesized a similar decrease in indigenous gut microbiota diversity, which may have contributed to the obesity epidemic. To investigate the changes in the composition and function of the gut microbiota in pregnant women over a period of 20 years. Altogether 124 pregnant women (41 overweight and matched 83 normal weight) pregnant in 1997, 2007 or 2017 were included in the study. The gut microbiota composition was assessed from fecal samples obtained at 32 weeks of gestation by 16S rRNA gene sequencing. Fecal short chain fatty acid (SCFA) profiles were measured by gas chromatography mass spectrometry (GC-MS). Distinct gut microbiota profiles were detected in pregnant women from 1997, 2007 and 2017 (PERMANOVA Bray-Curtis R2 = 0.029, p = 0.001). The women pregnant in 1997 exhibited significantly higher microbiota richness and diversity as compared to those pregnant in 2007 and 2017. The total concentration of fecal SCFAs was significantly higher in the pregnant women in 1997 compared to those in 2007 and 2017. Significant differences in gut microbiota composition between normal weight and overweight women were manifest in 1997 but not in 2007 or 2017. The decrease in intestinal microbiota richness and diversity over two decades occurred in parallel with the decline in biodiversity in our natural surroundings. It appears that the gut microbiota of pregnant women has changed over time to a composition typical for overweight individuals.
Animal models of Parkinson’s disease: bridging the gap between disease hallmarks and research questions
Authors: Axelle Dovonou, Cyril Bolduc, Victoria Soto Linan, Charles Gora, Modesto R. Peralta III, Martin Lévesque
Journal: Translational Neurodegeneration (2023)

Abstract Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. More than 200 years after its first clinical description, PD remains a serious affliction that affects a growing proportion of the population. Prevailing treatments only alleviate symptoms; there is still neither a cure that targets the neurodegenerative processes nor therapies that modify the course of the disease. Over the past decades, several animal models have been developed to study PD. Although no model precisely recapitulates the pathology, they still provide valuable information that contributes to our understanding of the disease and the limitations of our treatment options. This review comprehensively summarizes the different animal models available for Parkinson’s research, with a focus on those induced by drugs, neurotoxins, pesticides, genetic alterations, α-synuclein inoculation, and viral vector injections. We highlight their characteristics and ability to reproduce PD-like phenotypes. It is essential to realize that the strengths and weaknesses of each model and the induction technique at our disposal are determined by the research question being asked. Our review, therefore, seeks to better aid researchers by ensuring a concrete discernment of classical and novel animal models in PD research.
Safety and efficacy of artesunate treatment in severely injured patients with traumatic hemorrhage. The TOP-ART randomized clinical trial
Authors: Joanna M. Shepherd, Jennifer Ross, Lourdes Anton, Claire Rourke, Adam R. Brentnall, Joel Tarning, Nicholas J. White, Christoph Thiemermann, Karim Brohi
Journal: Intensive Care Medicine (2023)

This study aimed at determining whether intravenous artesunate is safe and effective in reducing multiple organ dysfunction syndrome in trauma patients with major hemorrhage.TOP-ART, a randomized, blinded, placebo-controlled, phase IIa trial, was conducted at a London major trauma center in adult trauma patients who activated the major hemorrhage protocol. Participants received artesunate or placebo (2:1 randomization ratio) as an intravenous bolus dose (2.4 mg/kg or 4.8 mg/kg) within 4 h of injury. The safety outcome was the 28-day serious adverse event (SAE) rate. The primary efficacy outcome was the 48 h sequential organ failure assessment (SOFA) score. The per-protocol recruitment target was 105 patients.The trial was terminated after enrolment of 90 patients because of safety concerns. Eighty-three participants received artesunate (n = 54) or placebo (n = 29) and formed the safety population and 75 met per-protocol criteria (48 artesunate, 27 placebo). Admission characteristics were similar between groups (overall 88% male, median age 29 years, median injury severity score 22), except participants who received artesunate were more shocked (median base deficit 9 vs. 4.7, p = 0.042). SAEs occurred in 17 artesunate participants (31%) vs. 5 who received placebo (17%). Venous thromboembolic events (VTE) occurred in 9 artesunate participants (17%) vs. 1 who received placebo (3%). Superiority of artesunate was not supported by the 48 h SOFA score (median 5.5 artesunate vs. 4 placebo, p = 0.303) or any of the trial's secondary endpoints.Among critically ill trauma patients, artesunate is unlikely to improve organ dysfunction and might be associated with a higher VTE rate.
A proteomics analysis of 5xFAD mouse brain regions reveals the lysosome-associated protein Arl8b as a candidate biomarker for Alzheimer’s disease
Authors: Annett Boeddrich, Christian Haenig, Nancy Neuendorf, Eric Blanc, Andranik Ivanov, Marieluise Kirchner, Philipp Schleumann, Irem Bayraktaroğlu, Matthias Richter, Christine Mirjam Molenda, Anje Sporbert, Martina Zenkner, Sigrid Schnoegl, Christin Suenkel, Luisa-Sophie Schneider, Agnieszka Rybak-Wolf, Bianca Kochnowsky, Lauren M. Byrne, Edward J. Wild, Jørgen E. Nielsen, Gunnar Dittmar, Oliver Peters, Dieter Beule, Erich E. Wanker
Journal: Genome Medicine (2023)

Alzheimer's disease (AD) is characterized by the intra- and extracellular accumulation of amyloid-β (Aβ) peptides. How Aβ aggregates perturb the proteome in brains of patients and AD transgenic mouse models, remains largely unclear. State-of-the-art mass spectrometry (MS) methods can comprehensively detect proteomic alterations, providing relevant insights unobtainable with transcriptomics investigations. Analyses of the relationship between progressive Aβ aggregation and protein abundance changes in brains of 5xFAD transgenic mice have not been reported previously.
Phase II Study of Olaparib and Temozolomide for Advanced Uterine Leiomyosarcoma (NCI Protocol 10250)
Authors: Matthew Ingham, Jacob B. Allred, Li Chen, Biswasjit Das, Bose Kochupurakkal, Katherine Gano, Suzanne George, Steven Attia, Melissa A. Burgess, Mahesh Seetharam, Sosipatros A. Boikos, Nam Bui, James L. Chen, Julia L. Close, Gregory M. Cote, Premal H. Thaker, S. Percy Ivy, Sminu Bose, Alan D'Andrea, Adrian Marino-Enriquez, Geoffrey I. Shapiro, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2023)

PURPOSE Uterine leiomyosarcoma (uLMS) is an aggressive subtype of soft-tissue sarcoma with frequent metastatic relapse after curative surgery. Chemotherapy provides limited benefit for advanced disease. Multiomics profiling studies have identified homologous recombination deficiency in uLMS. In preclinical studies where olaparib and temozolomide provided modest activity, the combination was highly effective for inhibiting uLMS tumor growth. PATIENTS AND METHODS NCI Protocol 10250 is a single-arm, open-label, multicenter, phase II study evaluating olaparib and temozolomide in advanced uLMS. Patients with progression on ≥1 prior line received temozolomide 75 mg/m 2 orally once daily with olaparib 200 mg orally twice a day both on days 1-7 in 21-day cycles. The primary end point was the best objective response rate (ORR) within 6 months. A one-stage binomial design was used. If ≥5 of 22 responded, the treatment would be considered promising (93% power; α = .06). All patients underwent paired biopsies that were evaluated with whole-exome sequencing (WES)/RNAseq and a RAD51 foci formation assay. RESULTS Twenty-two patients were evaluable. The median age was 55 years, and 59% had received three or more prior lines. Best ORR within 6 months was 23% (5 of 22). The overall ORR was 27% (6 of 22). The median progression-free survival (mPFS) was 6.9 months (95% CI, 5.4 months to not estimable). Hematologic toxicity was common (grade 3/4 neutropenia: 75%; thrombocytopenia: 32%) but manageable with dose modification. Five of 16 (31%) of tumors contained a deleterious homologous recombination gene alteration by WES, and 9 of 18 (50%) were homologous recombination-deficient by the RAD51 assay. In an exploratory analysis, mPFS was prolonged for patients with homologous recombination-deficient versus homologous recombination-proficient tumors (11.2 v 5.4 months, P = .05) by RAD51. CONCLUSION Olaparib and temozolomide met the prespecified primary end point and provided meaningful clinical benefit in patients with advanced, pretreated uLMS.
Implementation of a Prevention Bundle to Decrease Rates of <i>Staphylococcus aureus</i> Surgical Site Infection at 11 Veterans Affairs Hospitals
Authors: Hiroyuki Suzuki, Eli N. Perencevich, Stacey Hockett Sherlock, Gosia S. Clore, Amy M. J. O’Shea, Graeme N. Forrest, Christopher D. Pfeiffer, Nasia Safdar, Christopher Crnich, Kalpana Gupta, Judith Strymish, Gio Baracco Lira, Suzanne Bradley, Jose Cadena-Zuluaga, Michael Rubin, Marvin Bittner, Daniel Morgan, Aaron DeVries, Kelly Miell, Bruce Alexander, Marin L. Schweizer
Journal: JAMA Network Open (2023)

Importance While current evidence has demonstrated a surgical site infection (SSI) prevention bundle consisting of preoperative Staphylococcus aureus screening, nasal and skin decolonization, and use of appropriate perioperative antibiotic based on screening results can decrease rates of SSI caused by S aureus , it is well known that interventions may need to be modified to address facility-level factors. Objective To assess the association between implementation of an SSI prevention bundle allowing for facility discretion regarding specific component interventions and S aureus deep incisional or organ space SSI rates. Design, Setting, and Participants This quality improvement study was conducted among all patients who underwent coronary artery bypass grafting, cardiac valve replacement, or total joint arthroplasty (TJA) at 11 Veterans Administration hospitals. Implementation of the bundle was on a rolling basis with the earliest implementation occurring in April 2012 and the latest implementation occurring in July 2017. Data were collected from January 2007 to March 2018 and analyzed from October 2020 to June 2023. Interventions Nasal screening for S aureus ; nasal decolonization of S aureus carriers; chlorhexidine bathing; and appropriate perioperative antibiotic prophylaxis according to S aureus carrier status. Facility discretion regarding how to implement the bundle components was allowed. Main Outcomes and Measures The primary outcome was deep incisional or organ space SSI caused by S aureus . Multivariable logistic regression with generalized estimating equation (GEE) and interrupted time-series (ITS) models were used to compare SSI rates between preintervention and postintervention periods. Results Among 6696 cardiac surgical procedures and 16 309 TJAs, 95 S aureus deep incisional or organ space SSIs were detected (25 after cardiac operations and 70 after TJAs). While the GEE model suggested a significant association between the intervention and decreased SSI rates after TJAs (adjusted odds ratio, 0.55; 95% CI, 0.31-0.98), there was not a significant association when an ITS model was used (adjusted incidence rate ratio, 0.88; 95% CI, 0.32-2.39). No significant associations after cardiac operations were found. Conclusions and Relevance Although this quality improvement study suggests an association between implementation of an SSI prevention bundle and decreased S aureus deep incisional or organ space SSI rates after TJAs, it was underpowered to see a significant difference when accounting for changes over time.
Breast Cancer Metastatic Progression Requires mRNA Posttranscriptional Suppression
Authors: Cinthia Claudia Amaya Ramirez, Fabricio Loayza-Puch
Journal: Cancer Research (2023)

Cancer cell survival is highly dependent on its metabolic reprogramming, which supports not only cell growth but also confers to the tumor cells characteristics to initiate migration and colonization. Among the different mechanisms that are involved, translational control plays a significant role in oncogenesis; however, its impact on cancer progression still remains poorly understood. A study by Navickas and colleagues revealed that the RNA-binding protein heterogeneous nuclear ribonucleoprotein C (HNRNPC) functions as a translational regulator, and its downregulation in highly metastatic cells leads to the lengthening of 3' untranslated regions in HNRNPC-bound mRNAs, resulting in translational repression mediated by the AGO-miRNA RNA-induced silencing complex.
Alcohol reshapes a liver premetastatic niche for cancer by extra- and intrahepatic crosstalk-mediated immune evasion
Authors: Xiaofang Qiu, Jiaqi Zhou, Hong Xu, Yongyin Li, Shudong Ma, Hang Qiao, Kangxin Zeng, Qiongqiong Wang, Jiahe Ouyang, Yuanhan Liu, Jian Ding, Yantan Liu, Junhao Zhang, Min Shi, Yulin Liao, Wangjun Liao, Li Lin
Journal: Molecular Therapy (2023)

Cancer metastatic organotropism is still a mystery. The liver is known to be susceptible to cancer metastasis and alcoholic injury. However, it is unclear whether and how alcohol facilitates liver metastasis and how to intervene. Here, we show that alcohol preferentially promotes liver metastasis in colon-cancer-bearing mice and post-surgery pancreatic cancer patients. The mechanism is that alcohol triggers an extra- and intrahepatic crosstalk to reshape an immunosuppressive liver microenvironment. In detail, alcohol upregulates extrahepatic IL-6 and hepatocellular IL-6 receptor expression, resulting in hepatocyte STAT3 signaling activation and downstream lipocalin-2 (Lcn2) upregulation. Furthermore, LCN2 promotes T cell-exhaustion neutrophil recruitment and cancer cell epithelial plasticity. In contrast, knocking out hepatocellular Stat3 or systemic Il6 in alcohol-treated mice preserves the liver microenvironment and suppresses liver metastasis. This mechanism is reflected in hepatocellular carcinoma patients, in that alcohol-associated signaling elevation in noncancerous liver tissue indicates adverse prognosis. Accordingly, we discover a novel application for BBI608, a small molecular STAT3 inhibitor that can prevent liver metastasis. BBI608 pretreatment protects the liver and suppresses alcohol-triggered premetastatic niche formation. In conclusion, under extra- and intrahepatic crosstalk, the alcoholic injured liver forms a favorable niche for cancer cell metastasis, while BBI608 is a promising anti-metastatic agent targeting such microenvironments.
A novel human papillomavirus and host DNA methylation score and detection of cervical adenocarcinoma
Authors: Ana Gradissimo, Megan A Clarke, Xiaonan Xue, Philip E Castle, Tina R Raine-Bennett, Mark Schiffman, Nicolas Wentzensen, Howard D Strickler, Robert D Burk
Journal: JNCI Journal of the National Cancer Institute (2023)

The widespread introduction of Pap testing in the 1960s was followed by substantial reductions in the incidence of cervical squamous cell cancer (SCC). However, the incidence of cervical adenocarcinoma (ADC) did not decrease, likely because of low Pap test sensitivity for ADC and adenocarcinoma in situ (AIS). This study assessed a novel human papillomavirus (HPV) and host DNA Methylation Score for AIS and ADC screening.
State‐of‐the‐art document on optimal contemporary management of cardiomyopathies
Authors: Petar M. Seferović, Marija Polovina, Giuseppe Rosano, Biykem Bozkurt, Marco Metra, Stephane Heymans, Wilfried Mullens, Johann Bauersachs, Karen Sliwa, Rudolf A. de Boer, Dimitrios Farmakis, Thomas Thum, Iacopo Olivotto, Claudio Rapezzi, Aleš Linhart, Domenico Corrado, Carsten Tschöpe, Ivan Milinković, Antoni Bayes Genis, Gerasimos Filippatos, Andre Keren, Milika Ašanin, Gordana Krljanac, Ružica Maksimović, Hadi Skouri, Tuvia Ben Gal, Brenda Moura, Maurizio Volterrani, Magdy Abdelhamid, Yuri Lopatin, Ovidiu Chioncel, Andrew J.S. Coats
Journal: European Journal of Heart Failure (2023)
Comprehensive profiling identifies tumour and immune microenvironmental differences in clinical subsets of cutaneous squamous cell carcinoma
Authors: Alesha A Thai, Richard J Young, Mathias Bressel, Christopher Angel, Lachlan McDowell, Albert Tiong, Nicholas W Bucknell, Andrew Fellowes, Huiling Xu, Anna Trigos, Danny Rischin, Benjamin J Solomon
Journal: British Journal of Dermatology (2023)

Abstract Background Cutaneous squamous cell carcinomas (cSCCs) are the second most diagnosed skin cancer worldwide; however, little is known about the pathobiological factors that contribute to the diverse clinical outcomes seen. Objectives To profile cSCCs comprehensively and identify the pathological processes that contribute to the disparities seen in their clinical behaviour. Methods We characterized the genomic, transcriptomic and immunohistochemical profiles of 211 cSCC tumours, including 37 cSCCs from immunocompromised patients. Results cSCCs from immunocompromised patients were characterized by a lack of B cells in the peritumoral stroma compared with immunocompetent patients. Further, an abundance of a memory B-cell-like population in the peritumoral stroma was associated with a better prognosis in all patients (immunocompetent and immunocompromised), as well as only immunocompetent patients. No differences in genetic ­variants, tumour mutational burden or mutational signatures were observed between cSCCs from immunocompetent and immunocompromised patients. Thus, differences in survival between cSCCs from immunocompromised patients and immunocompetent patients are not likely to be driven by tumour genomic factors, but may be associated with differential host immune response. cSCC not from a primary head and neck site had lower tumour mutational burden and exhibited upregulation of the epithelial–mesenchymal transition programme compared with head and neck cSCC. Both factors were implicated with poorer responses to immune checkpoint inhibition, and the latter with poorer survival. Conclusions We identified tumour and host immune factors that contribute to the disparate clinical behaviour of cSCC, with broad translational application, including prognostication, treatment prediction to current therapies and the identification of novel anticancer therapy approaches in cSCC.
MYD88L265P augments proximal B-cell receptor signaling in large B-cell lymphomas via an interaction with DOCK8
Authors: Elisa Mandato, Qingsheng Yan, Jing Ouyang, Julia Paczkowska, Yan Qin, Yansheng Hao, Kamil Bojarczuk, Julia Hansen, Björn Chapuy, Scott J. Rodig, Sumbul Jawed Khan, Robert A. Redd, Margaret A. Shipp
Journal: Blood (2023)